Activation of CXCR2 by Extracellular Matrix Degradation Product Acetylated Pro-Gly-Pro Has Therapeutic Effects against Sepsis

Title
Activation of CXCR2 by Extracellular Matrix Degradation Product Acetylated Pro-Gly-Pro Has Therapeutic Effects against Sepsis
Author(s)
백석환김상두[김상두]이하영[이하영]심재웅[심재웅]김학정[김학정]유영현[유영현]박준성[박준성]Zabel Brian A[Zabel Brian A]배외식[배외식]
Keywords
INFLAMMATORY RESPONSE; INDUCED APOPTOSIS; CYTOKINE PROFILE; CECAL LIGATION; IFN-GAMMA; RECEPTOR; IDENTIFICATION; INTERLEUKIN-8; CHEMOATTRACTANT; NEUTROPHILS
Issue Date
201107
Publisher
AMER THORACIC SOC
Citation
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, v.184, no.2, pp.243 - 251
Abstract
Rationale: Acetylated Pro-Gly-Pro (Ac-PGP) is an endogenous degradation product of extracellular collagen that binds to leukocyte-expressed chemoattractant receptor CXCR2. Although certain agents that block CXCR2-mediated signaling protect against experimental sepsis, the roles of Ac-PGP and CXCR2 in sepsis are unclear. Objectives: To investigate the role of Ac-PGP and its receptor, CXCR2, in murine models of cecal ligation and puncture (CLP)induced polymicrobial sepsis and organ injury. Methods: The impact of in vivo Ac-PGP treatment on animal survival after induction of experimental sepsis was assessed. Vital organ inflammation and immune cell apoptosis were evaluated by histology, and the modulation of proinflammatory cytokine production and bactericidal activity by Ac-PGP in mouse and human blood leukocytes was measured. Measurements and Main Results: The activation of CXCR2 by tripeptide agonist Ac-PGP dramatically improved survival in three experimental sepsis models. Ac-PGP elicited bactericidal activity via the generation of hydrogen peroxide, inhibited lung inflammation, and reduced immune cell apoptosis. Fluorescein isothiocyanate-labeled PGP bound directly to CXCR2, and the protective effect of Ac-PGP in sepsis was abolished in CXCR2-deficient mice. Ac-PGP treatment enhanced the production of type 1 cytokines (IFN-gamma and IL-12) but inhibited the production of proinflammatory cytokines (tumor necrosis factor [TNF]-alpha, IL-1 beta, and IL-6) in vivo. In vitro, Ac-PGP directly increased IFN-gamma production and decreased the LPS-stimulated production of TNF-alpha by mouse splenocytes and human leukocytes. Furthermore, direct treatment of LPS-stimulated splenocytes with IFN-gamma resulted in diminished secretion of TNF-alpha and IL-6. Conclusions: CXCR2 and Ac-PGP are thus novel target and starting molecules, respectively, for the development of therapeutic agents against sepsis.
URI
http://hdl.handle.net/YU.REPOSITORY/24872http://dx.doi.org/10.1164/rccm.201101-0004OC
ISSN
1073-449X
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의과대학 > 생화학.분자생물학교실 > Articles
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